The effects of Mycobacterium tuberculosis on T cell responsiveness in granulomas

<div>Background:</div><div>The pathologic hallmark of infection with <i>Mycobacterium tuberculosis</i> (Mtb) are granulomas, collections of host immune cells (e.g. macrophages and T cells) that organize in an attempt to contain and eliminate the infection. Since granulomas are the sites of infection within lungs, we expect them to be enriched substantially in Mtb-responsive T cells (producing cytokines in response to Mtb). Surprisingly, a low frequency of Mtb-responsive T cells (~ 10%) in granulomas have been observed. As Mtb-specific T cells are key to clearance of the pathogen, it is important to determine why the frequency of functional T cells in granulomas is so low. One hypothesis is that T cells are being down-regulated directly by Mtb.</div><div><br></div><div>Methods:</div><div>To study this dynamic, we use a Multi-Scale Modeling (MSM) approach. Our lab has previously created an agent-based model (ABM), known as <i>GranSim</i>, that tracks bacteria as individual immune cells as agents. In addition, we have an existing system of ODEs that captures Mtb-mediated down-regulation of MHCII presentation of peptides in macrophages that we have previously published. We create a novel hybrid, multi-scale computational model by linking these two models putting these equations directly into antigen presenting cells within <i>GranSim</i> resulting in a MSM that spans scales from intracellular to tissue.</div><div><br></div><div>Results:</div><div>Through uncertainty and sensitivity analysis, we identified a number of critical input parameters that impact model outcomes. At the molecular level, MHCII presentation of peptides during 2 days post infection is most affected by association/dissociation rates of IFNγ, which affects MHCII transcription rates. Downstream of that, decreases in MHCII peptide complexes are influenced most by IFNγ and exogenous antigen degradation rates, while increases are influenced by exogenous antigen pinocytosis and processing rates. At the cellular level, increased IFNγ concentrations are most sensitive to T cell levels between 30-40 days, while sensitivity of the binding threshold of MHCII peptide complexes that are required to activate T cells decreases in relation to T cell levels. Increased concentrations of Mtb antigens is most sensitive to granuloma size and infected macrophage, TNF-induced apoptosis rates from 25-50 days.</div><div><br></div><div>Discussion:</div><div>This work provides insights into mechanisms that could be either enhanced or inhibited to therapeutically increase frequencies of Mtb-responsive T cells and at the same to helping to understand what mechanisms may be contributing to the extremely low levels of responsiveness.</div>